1. Field of the Invention
This invention relates to the use of certain known compounds for the novel purpose of healing wounds and treating certain other conditions associated with the accumulation of extracellular matrix In tissue.
2. Description of the Related Art
It is a problem that although wounds in humans and other mammals usually heal reasonably quickly, unsightly scar tissue is often formed. It is known that growth factors are implicated in fibrotic disorders. Various proposals have been made to ameliorate the effects of fibrotic disorders by administering either the growth factor or antibodies thereto. See, for example W. A. Border et al., Nature 346 371-374 (1990), who showed that extracellular matrix production in acute mesangial proliferative glomerulonephritis (inflammation of the kidney believed caused by immunological injury to cells) is associated with increased production of transformlng growth factor (TGF)-.beta.1 and suppressed by administering anti-TGF-.beta.1. E. Kovacs, Immunology Today 12 (1) 17-23 (1991) concludes that blocking the effects of certain cytokines (such as TNF-.alpha.) with antibodies has diminished fibrosis in animal models of tissue injury. PCT Application Publication No. WO91/04748 (La Jolla Cancer Research Foundation) proposes to treat pathologies associated with accumulation of extracellular matrix in tissue with platelet derived growth factor (PGDF) or with antibodies to TGF-.beta.1. The diseases treated are in general fibrotic diseases and include glomerulonephritis, adult respiratory distress syndrome, cirrhosis of the liver, fibrocytic disease, fibrosis, fibrotic cancers, fibroids, fibroadenomas and fibrosarcomas. Other fibrotic conditions are mentioned. Also, the method can be used to treat or prevent excessive scarring such as keloid scars (hard, irregular scar tissue in the skin which forms when a wound is under tension) and/or is produced in genetically pre-disposed people. H. Shah, D. H. Foreman and M. W. J. Ferguson, The Lancet 339, 213-214 (Jan 25, 1992), describe the control of scarring in wounds by administering antibody which neutralises TGF-.beta.1 and -.beta.2.
The biological mechanisms by which the growth factors operate is not well understood, see C. C. Bascom et. al., Molecular and Cellular Biology 9, 5508-5515 (1989).
It is known that TGF-.beta.1 is synthesised as a pre-pro-protein of 390 amino acids which is converted to mature protein by cleavage between aa residues 278 and 279. However, TGF-.beta.1 isolated in vivo is found predominantly as a high molecular weight latent complex (LTGF .beta.1) in which the pro-region is still associated with the mature molecule, despite the cleavage of the peptide bond. TGF-.beta.2 and .beta.-3 also have latent forms. All have been shown to bind to a plasma membrane receptor called the cation-independent mannose-6-phosphate/insulin-like growth factor II receptor. Binding occurs through mannose-6-phosphate residues attached at glycosylation sites within the pro-region and, in the case of TGF-.beta.1 and TGF-.beta.2, has been shown to be inhibited by antibodies to the receptor. In the case of TGF-.beta.1, binding is inhibited by mannose-6-phosphate itself. See P. A. Dennis and D. B. Rifkin, Proc. Natl. Acad. Sci. USA, 88, 580-584 (1991), M. N. Lioubin, H. Marquardt, R. Roth, K. S. Kovacina and A. F. Purchio, Journal of Cellular Biochemistry 45, 112-121 (1991) and K. Miyazano et al., Annals of the New York Academy of Sciences 593, 51-58 (1990). It has not been clear whether it is desirable to prevent the generation in vivo of the mature active forms of TGFs or whether mannose-6-phosphate receptor binding is the only means of activating the mature protein. It has been suggested in the literature that TGF-.beta.1 becomes activated under various pH conditions: see "The Transforming Growth Factor .beta.s" in "Peptide Growth Factors and Their Receptors 1" (eds. M. B. Sporn and A. B. Roberts), Springer Verlag 1990, pages 419-472, at page 432, and references cited therein. See also K. Miyazano et. al., supra, at page 55, who mention activation by enzymes such as plasmin, cathepsin D and a glycosldase. These authors also suggest that high concentrations of sialic acid or mannose-6-phosphate activate the latent form.
Further prior art, the relevance of which is not apparent without knowledge of the invention, is mentioned below after the "Summary of the invention" section.